Although primary lateral sclerosis (PLS) is generally considered to be a motor neuron disorder, its relationship to amyotrophic lateral sclerosis (ALS) and other motor neuron disorders is uncertain. PLS differs from ALS in its duration, with a median survival of more than a decade, in contrast to the median survival of 3-5 years in ALS. The long survival corresponds to the restriction of disease to the corticospinal, or upper motor neurons, of the brain. Understanding whether PLS and ALS represent different manifestations of the same disease, and factors that reduce disease progression are questions being examined in our group. In FY11 we completed the analysis of a multi-year cross-sectional study to examine structural differences between PLS and ALS patients with quantitative imaging techniques. We had previously shown that measurements of the fractional anisotropy and mean diffusivity of the white matter of corticospinal tract and corpus callosum could be made reliably in diffusion tensor MRI images (DTI) and were stable over a years time in healthy controls. Using the same methodology, we found that the pattern of corticospinal white matter alteration differed between ALS and PLS patients and from healthy age-matched controls. A consistent finding was that fractional anisotropy in the motor fibers of the corpus callosum in both PLS and ALS patients. This finding indicates that at least two populations of cortical projection neurons undergo degeneration in motor neuron disorders. We also completed data collection for a longitudinal imaging component from approximately half of the PLS and ALS patients in the cross-sectional study, and the analysis of these data is underway. A collaboration was begun with investigators at Columbia University as part of a multicenter study examining the role of oxidative stress in progression of motor neuron diseases. In FY11 we reached 80% of the accrual target for PLS patients, whose progression will be followed annually with clinical measures at NIH, and with epidemiological surveys and markers of oxidative stress in biofluids at Columbia over a 3-year period.